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The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism

Genetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics Eng...

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Autores principales: Michaud, Vincent, Lasseaux, Eulalie, Green, David J., Gerrard, Dave T., Plaisant, Claudio, Fitzgerald, Tomas, Birney, Ewan, Arveiler, Benoît, Black, Graeme C., Sergouniotis, Panagiotis I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270319/
https://www.ncbi.nlm.nih.gov/pubmed/35803923
http://dx.doi.org/10.1038/s41467-022-31392-3
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author Michaud, Vincent
Lasseaux, Eulalie
Green, David J.
Gerrard, Dave T.
Plaisant, Claudio
Fitzgerald, Tomas
Birney, Ewan
Arveiler, Benoît
Black, Graeme C.
Sergouniotis, Panagiotis I.
author_facet Michaud, Vincent
Lasseaux, Eulalie
Green, David J.
Gerrard, Dave T.
Plaisant, Claudio
Fitzgerald, Tomas
Birney, Ewan
Arveiler, Benoît
Black, Graeme C.
Sergouniotis, Panagiotis I.
author_sort Michaud, Vincent
collection PubMed
description Genetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics England 100,000 Genomes Project and from a cohort of 1313 individuals with albinism aiming to gain insights into the genetic architecture of this archetypal rare disorder. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.−301C>T [rs4547091], modulates the penetrance of a prevalent, albinism-associated missense change, TYR c.1205G>A (p.Arg402Gln) [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[−301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and with increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants can increase diagnostic yield and can help inform genetic counselling in families with albinism.
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spelling pubmed-92703192022-07-10 The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism Michaud, Vincent Lasseaux, Eulalie Green, David J. Gerrard, Dave T. Plaisant, Claudio Fitzgerald, Tomas Birney, Ewan Arveiler, Benoît Black, Graeme C. Sergouniotis, Panagiotis I. Nat Commun Article Genetic diseases have been historically segregated into rare Mendelian disorders and common complex conditions. Large-scale studies using genome sequencing are eroding this distinction and are gradually unmasking the underlying complexity of human traits. Here, we analysed data from the Genomics England 100,000 Genomes Project and from a cohort of 1313 individuals with albinism aiming to gain insights into the genetic architecture of this archetypal rare disorder. We investigated the contribution of protein-coding and regulatory variants both rare and common. We focused on TYR, the gene encoding tyrosinase, and found that a high-frequency promoter variant, TYR c.−301C>T [rs4547091], modulates the penetrance of a prevalent, albinism-associated missense change, TYR c.1205G>A (p.Arg402Gln) [rs1126809]. We also found that homozygosity for a haplotype formed by three common, functionally-relevant variants, TYR c.[−301C;575C>A;1205G>A], is associated with a high probability of receiving an albinism diagnosis (OR>82). This genotype is also associated with reduced visual acuity and with increased central retinal thickness in UK Biobank participants. Finally, we report how the combined analysis of rare and common variants can increase diagnostic yield and can help inform genetic counselling in families with albinism. Nature Publishing Group UK 2022-07-08 /pmc/articles/PMC9270319/ /pubmed/35803923 http://dx.doi.org/10.1038/s41467-022-31392-3 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Michaud, Vincent
Lasseaux, Eulalie
Green, David J.
Gerrard, Dave T.
Plaisant, Claudio
Fitzgerald, Tomas
Birney, Ewan
Arveiler, Benoît
Black, Graeme C.
Sergouniotis, Panagiotis I.
The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
title The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
title_full The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
title_fullStr The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
title_full_unstemmed The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
title_short The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism
title_sort contribution of common regulatory and protein-coding tyr variants to the genetic architecture of albinism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9270319/
https://www.ncbi.nlm.nih.gov/pubmed/35803923
http://dx.doi.org/10.1038/s41467-022-31392-3
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